Fibrosis In Crohn's Disease Research Articles

Contemporary Imaging Assessment of Strictures and Fibrosis in Crohn Disease, With Focus on Quantitative Biomarkers: From the AJR Special Series on Imaging of Fibrosis.

Patients with Crohn disease commonly have bowel strictures develop, which exhibit varying degrees of inflammation and fibrosis. Differentiation of the distinct inflammatory and fibrotic components of strictures is key for the optimization of therapeutic management and for the development of antifibrotic drugs. Cross-sectional imaging techniques, including ultrasound, CT, and MRI, allow evaluation of the full thickness of the bowel wall as well as extramural complications and associated mesenteric abnormalities. Although promising data have been reported for a range of novel imaging biomarkers for detection of fibrosis and quantification of the degree of fibrosis, these biomarkers lack sufficient validation and standardization for clinical use. Additional methods, including PET with emerging radiotracers, artificial intelligence, and radiomics, are also under investigation for stricture characterization. In this review, we highlight the clinical relevance of identifying fibrosis in Crohn disease, review the histopathologic aspects of strictures in Crohn disease, summarize the morphologic imaging findings of strictures, and explore contemporary developments in the use of cross-sectional imaging techniques for detecting and characterizing intestinal strictures, with attention given to emerging quantitative biomarkers.

The Promise of Single-Cell RNA Sequencing to Redefine the Understanding of Crohn's Disease Fibrosis Mechanisms.

Crohn's disease (CD) is a chronic inflammatory bowel disease with a high prevalence throughout the world. The development of Crohn's-related fibrosis, which leads to strictures in the gastrointestinal tract, presents a particular challenge and is associated with significant morbidity. There are currently no specific anti-fibrotic therapies available, and so treatment is aimed at managing the stricturing complications of fibrosis once it is established. This often requires invasive and repeated endoscopic or surgical intervention. The advent of single-cell sequencing has led to significant advances in our understanding of CD at a cellular level, and this has presented opportunities to develop new therapeutic agents with the aim of preventing or reversing fibrosis. In this paper, we discuss the current understanding of CD fibrosis pathogenesis, summarise current management strategies, and present the promise of single-cell sequencing as a tool for the development of effective anti-fibrotic therapies.

Evaluation of Intestinal Fibrosis with 68Ga-FAPI PET/MR Enterography in Crohn Disease.

Background In Crohn disease, differentiation between active intestinal inflammation and fibrosis has implications for treatment, but current imaging modalities are not reliably accurate. Purpose To evaluate the predictive value of gallium 68 (68Ga)-labeled fibroblast activation protein inhibitor (FAPI) PET/MR enterography for the assessment of bowel wall fibrosis in Crohn disease. Materials and Methods In this prospective single-center study, consecutive participants with Crohn disease and obstructive symptoms underwent preoperative 68Ga-FAPI PET/MR enterography from May 2021 to January 2022. Histopathologic analysis of resected bowel segments was performed to grade active inflammation (A0-A2) and fibrosis (F0-F2), which served as the reference standard. The fibroblast activation protein (FAP) expression in bowel wall layers was analyzed immunohistochemically for each layer. 68Ga-FAPI-derived maximum standardized uptake value (SUVmax) was compared with histopathologic results by using mixed-model analysis of variance and Bonferroni-corrected post hoc tests. Results In 14 participants (mean age, 45 years ± 9 [SD]; 10 men), fibrosis was diagnosed histopathologically in 28 of 51 bowel segments (grade F1, n = 14; grade F2, n = 14). Mean SUVmax was higher in segments with fibrosis than without (7.6 vs 2.0; P < .001). In severe fibrosis, mean SUVmax was higher than in mild to moderate fibrosis (8.9 ± 0.9 vs 6.2 ± 0.9; P = .045). Bowel segments with isolated active inflammation had lower mean 68Ga-FAPI uptake than segments with combined active inflammation and fibrosis (SUVmax, 3.2 ± 0.4 vs 8.1 ± 0.1; P = .005). With an SUVmax cutoff value of 3.5, the area under the receiver operating characteristic curve for the prediction of fibrosis was 0.94 (95% CI: 0.9, 1.0), with sensitivity of 26 of 28 segments (93%) and specificity of five of six segments (83%). 68Ga-FAPI-derived SUVmax correlated with FAP expression across all bowel layers (R2 = 0.50, P < .001). Conclusion Higher gallium 68 fibroblast activation protein inhibitor uptake at PET/MR enterography was associated with histopathologically assessed bowel wall fibrosis in participants with Crohn disease, suggesting diagnostic potential for treatment decisions. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by O'Shea in this issue.

Potential Role of Epithelial Endoplasmic Reticulum Stress and Anterior Gradient Protein 2 Homologue in Crohn's Disease Fibrosis.

Intestinal fibrosis is a common complication of Crohn's disease [CD]. It is characterised by an accumulation of fibroblasts differentiating into myofibroblasts secreting excessive extracellular matrix. The potential role of the intestinal epithelium in this fibrotic process remains poorly defined. We performed a pilot proteomic study comparing the proteome of surface epithelium, isolated by laser-capture microdissection, in normal and fibrotic zones of resected ileal CD strictures [13 zones collected in five patients]. Proteins of interests were validated by immunohistochemistry [IHC] in ileal and colonic samples of stricturing CD [n = 44], pure inflammatory CD [n = 29], and control [n = 40] subjects. The pro-fibrotic role of one selected epithelial protein was investigated through in-vitro experiments using HT-29 epithelial cells and a CCD-18Co fibroblast to myofibroblast differentiation model. Proteomic study revealed an endoplasmic reticulum [ER] stress proteins increase in the epithelium of CD ileal fibrotic strictures, including anterior gradient protein 2 homologue [AGR2] and binding-immunoglobulin protein [BiP]. This was confirmed by IHC. In HT-29 cells, tunicamycin-induced ER stress triggered AGR2 intracellular expression and its secretion. Supernatant of these HT-29 cells, pre-conditioned by tunicamycin, led to a myofibroblastic differentiation when applied on CCD-18Co fibroblasts. By using recombinant protein and blocking agent for AGR2, we demonstrated that the secretion of this protein by epithelial cells can play a role in the myofibroblastic differentiation. The development of CD fibrotic strictures could involve epithelial ER stress and particularly the secretion of AGR2.

Cross-sectional imaging for assessing intestinal fibrosis in Crohn's disease.

More than 30% of patients with Crohn's disease (CD) develop fibrotic strictures in the bowel as the disease progresses. Excessive deposition of extracellular matrix components in the submucosa and smooth muscle hypertrophy or hyperplasia are the main features of fibrosis in CD. Cross-sectional imaging technology provides a wealth of information on the anatomy, histological composition, and physiological function of the bowel, allowing for a non-invasive and complete evaluation of associated abnormalities. This review summarizes recent advances in and the potential technologies of cross-sectional imaging for assessing intestinal fibrosis in CD, including ultrasound imaging, computed tomography, and magnetic resonance imaging.

Parathyroid Hormone–Like Hormone Induces Epithelial-to-Mesenchymal Transition of Intestinal Epithelial Cells by Activating the Runt-Related Transcription Factor 2

Epithelial-to-mesenchymal transition (EMT) is a key contributor to fibroblast activation in fibrosis of multiple organs, including the intestine. Parathyroid hormone-like hormone (PTHLH) is an important factor in renal fibrosis and regulates several processes, including EMT. Herein, we investigated the role of PTHLH-induced EMT in intestinal fibrosis associated with Crohn disease. The expression levels of the EMT-related proteins, PTHLH, and parathyroid hormone receptor 1 (PTH1R) in intestinal tissues were determined by immunohistochemistry, and our results revealed that PTHLH and PTH1R were significantly elevated and associated with EMT marker expression. Moreover, neutralizing PTH1R and antagonizing PTHLH bioactivity prevented transforming growth factor-β1-induced EMT. PTH1R can propagate the protein kinase A (PKA) signal and activate downstream nuclear transcription factors, including runt-related transcription factor 2 (Runx2). In addition, lentiviral vector-PTHLH-treated mice were highly sensitive to 2,4,6-trinitrobenzene sulfonic acid, and analysis of the PTHLH-PTH1R axis revealed the involvement of PKA-Runx2 in PTHLH-induced EMT. Our results indicate that PTHLH triggered EMT in intestinal epithelial cells through the PKA-Runx2 pathway, which might serve as a therapeutic target for intestinal fibrosis in Crohn disease.

Susceptibility genes and serum markers of intestinal fibrosis in Crohn disease

Crohn disease (CD) is a chronic inflammatory disease which progressively affects the digestive tract with unknown etiology. During the disease course, intestinal fibrosis will gradually develop in many CD patients and results in irreversible fibrosis stricture, causing refractory abdominal pain and even intestinal obstruction, and necessitating one or more surgical interventions. Thus far the exact etiology of CD remains unknown. It is believed that genetic, environmental and immunologic factors are involved, which may also predict the development of intestinal fibrosis. Recent studies have found the association of mutations in genes, such as NOD2, ATG16L1, CX3CR1, IL-23R and MMP3 with the fibrogenic phenotype of CD. In addition, serum extracellular matrix molecules, growth factors, miRNAs and microbial antibodies have also been linked to the fibrogenesis in CD patients, however the results of researches were divergent. Therefore it is of significance to explore noninvasive markers of intestinal fibrosis with high sensitivity and specificity, and the high-throughput proteomic technique may be an approach that deserves further investigation. Screening the high-risk patients for the fibrostenotic phenotype of CD by susceptibility genes, and early detection of intestinal fibrosis using noninvasive serum markers, will help improve the treatment outcomes and reduce the surgical rates. The article aims at summarizing the current susceptibility genes and serum markers of intestinal fibrosis in CD.

Real time strain elastography accurately dfferentiates between inflammatory and fibrotic strictures in Crohn's disease

Purpose: There are no reliable, non-invasive imaging techniques that can differentiate between inflammation and fibrosis in Crohn Disease (CD). Strain Elastography (SE) via transcutaneous ultrasound is a non-invasive technique for assessing strictures. The purpose of this study is to evaluate the accuracy of real-time SE for the characterisation of CD strictures in comparison to histopathological assessment of surgical resection specimens.

Effect of moxibustion on expressions of TGF-β and Smad4 in colonic mucosa of rats with intestinal fibrosis in Crohn disease

Objective To observe the effect of moxibustion on the expressions of transforming growth factor-β (TGF-β) protein, and Smad4 protein and mRNA in rats with intestinal fibrosis in Crohn disease (CD), and to discuss the action mechanism of acupuncture-moxibustion in treating intestinal fibrosis in CD from the perspective of TGF-β/Smads signal pathway.

Mast cells and eosinophils have a potential profibrogenic role in Crohn disease

Background: Mast cells and eosinophils have an important role in allergic inflammation and probably also in chronic inflammatory diseases resulting in fibrosis, such as Crohn disease where fibrosis is present as strictures. The involvement of mast cells and eosinophils in Crohn disease fibrosis was investigated. Methods: Biopsies from diseased foci were stained for mast cells, eosinophils, anti‐collagen type IV and VIII, laminin and α‐smooth muscle actin (α‐SMA) (IHC). Fibroblasts outgrown from the biopsies and a normal fetal intestinal fibroblast line were cultured in the presence of the human mast cell line HMC‐1, or of human peripheral blood eosinophil (MACS, purity > 98%) sonicates, or of selected mediators. Fibroblast proliferation (3H‐thymidine), collagen synthesis ([3H]‐proline) and collagen gel contraction were evaluated. Results: Mast cells were present in all the biopsies and only faintly positive for extra cellular matrix (ECM) products. Pronounced eosinophilia was detected in only two cases. Mast cell sonicates increased both Crohn disease (α‐SMA positive) and control fibroblast proliferation, decreased collagen production and increased collagen gel contraction. Eosinophil sonicates increased fibroblast proliferation, gel contraction and collagen production. TNF‐α decreased collagen production. Histamine, tryptase and chymase had no influence. Conclusions: These in vitro data show that mast cells and eosinophils could be involved in modulating Crohn disease fibrosis by directly influencing intestinal fibroblast properties.

Intestinal fibrosis in human and experimental inflammatory bowel disease

Fibrosis is a serious complication of Crohn disease for which there is no effective therapy. It is unclear why fibrosis, particularly fibrosis of the mucosal layer, develops in Crohn disease and not in ulcerative colitis. Smooth muscle cells, subepithelial myofibroblasts, and fibroblasts have traditionally been considered mediators of fibrosis, but new information points to a role of interstitial cells of Cajal and mast cells. Recent evidence about the role of each of these cell types in fibrosis in Crohn disease or other inflammatory bowel diseases is described. Hypothetical models to describe how altered function of these cells could underlie fibrosis of the mucosa or submucosal layers are presented. Fibrosis is not well characterized in any animal model of inflammatory bowel disease. The merits of several animal models for defining the mechanisms of inflammation-induced intestinal fibrosis are reviewed.